Currently there are numerous controlled release formulations on the market that contain various bioactive agents, such as GnRH analogs, human growth hormone, risperidone, and somatostatin analogs of which octreotide acetate is an example. Such formulations are preferred by physicians and veterinarians and by their patients because they reduce the need for multiple injections. Unfortunately, there are many problems with the formulations for controlled release compositions such as the fact that many popular bioactive agents are not good candidates for controlled release compositions due to their substantial water solubility. The use of highly soluble bioactive agents may result in low drug content and an undesirable “burst” of bioactive agent upon contact with an aqueous solution, such as by administration to a patient or introduction to a physiological medium, which often limits the useable content of bioactive agent achievable in practice.
Various methods of solving the water solubility problem have been devised with some success. One such effort is disclosed in U.S. Pat. No. 5,776,885 by Orsolini et al. Orsolini converted water soluble peptides to their water insoluble addition salts with pamoic, tannic or stearic acid prior to their encapsulation in sustained release compositions. Encapsulation within a polymer matrix is then performed by dispersing the water insoluble peptide in a polymer solution and forming controlled release compositions via either extrusion or a cumbersome coacervation method. One disadvantage of this approach is the requirement to obtain the water insoluble addition salt prior to encapsulation within a polymer matrix. Furthermore, it was discovered in the present work that when pre-formed addition salts were employed in an emulsion process to form microparticles the result was release of substantial amounts of modified or degraded peptide from the composition when placed in an aqueous physiological buffer. Modification was in the form of undesirable acylation of bioactive agent.
Controlled release compositions with a high drug load, low burst effect upon administration, and minimum degradation of the bioactive agent are greatly needed to realize the benefits of these types of compositions as human or veterinary therapeutics.